KR102304910B1 - Stable pharmaceutical composition comprising candesartan - Google Patents

Abstract

The present invention relates to single agents and combinations of candesartan or candesartan cilexetil. The present invention has excellent solubilization and stability of a main component. In particular, since the initial dissolution of candesartan or candesartan cilexetil is excellent, there is an advantage in the expression of efficacy.

Description

Stable pharmaceutical composition containing candesartan {STABLE PHARMACEUTICAL COMPOSITION COMPRISING CANDESARTAN}

The present invention relates to formulations comprising candesartan. Specifically, the present invention relates to candesartan single agent and candesartan combination agent.

[Candesartan]

Candesartan is 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxyl of Formula 1 it's a mountain

[Formula 1]

Candesartan is an angiotensin II receptor antagonist, and is an effective substance in the treatment of circulatory diseases such as hypertension, heart disease, seizures, stroke, or nephritis.

Candesartan is formulated as candesartan cilexetil of the following formula (2) in the form of a prodrug due to a very low absorption rate when administered orally.

[Formula 2]

Candesartan cilexetil is (±)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl-2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)[ 1,1'-biphenyl]-4-yl]methyl]-1H-benzimidazole-7-carboxylate, which is a substance that liberates cilexetil when absorbed in the gastrointestinal tract and is hydrolyzed to the active substance candesartan .

Candesartan cilexetil is a white to off-white powder, almost insoluble in water and ethanol. In addition, it is known that the stability is rapidly reduced due to the compression pressure and heat generated in the process of formulating into tablets.

In the meantime, studies on formulation design methods to increase the stability of candesartan cilexetil and improve bioavailability according to physical changes in the formulation process have been conducted.

For example, Korean Patent Application Laid-Open No. 10-1992-0021902 discloses hydrocarbons having a melting point of 20 to 90 ° C., higher fatty acids, higher alcohols, fatty acid esters of polyhydric alcohols, and higher polyhydric alcohols to improve the stability of candesartan cilexetil. A method of formulating by mixing an oily phase material selected from the group consisting of a polymer or copolymer of ether and alkylene oxide is introduced. However, in the case of formulation by mixing oily phase substances, it is difficult to constantly control the release characteristics of candesartan cilexetil, which is poorly soluble, under the influence of oily phase substances. In addition, it may be difficult to maintain a constant quality such as appearance or dissolution pattern as the oily phase material is melted by the heat generated during the formulation process such as the tableting process. have.

US Patent Publication No. 2008-01188564 introduces a method of preventing decomposition of active ingredients during tableting by post-mixing carrageenan, a hydrophilic colloidal forming material, as a stabilizer in the process just before tableting. However, when using carrageenan that forms a hydrophilic colloidal gel, there is a problem in that the initial drug release is delayed, and there is a limitation in that it is difficult to achieve a uniform mixing degree of carrageenan that is mixed with granules containing candesartan cilexetil after mixing.

Korean Patent Laid-Open Publication No. 10-2011-0062278 discloses that after candesartan cilexetil is refined, isomalt is blended as a stabilizer, and polyvinyl alcohol-polyethylene glycol graft copolymer (Kolicot IAL) is used as a binder and solubilizer. Here's how to use it. According to the literature, isomalt can improve the physico-chemical stability of candesartan cilexetil than other stabilizers, and granules must be prepared together with polyvinyl alcohol-polyethylene glycol graft copolymer to contain various excipients and candesartan. It is said that the stability and pharmacokinetics of candesartan cilexetil can be improved because cilexetil can form granules in a uniform amount. However, in this document, there is no stability comparison result with conventional commercial preparations, so it cannot be confirmed whether the stability is improved. In fact, the silylated microcrystalline cellulose (Comparative Examples 1 and 2 of the corresponding literature), which is suggested to have a less stability effect than isomalt in the literature, did not significantly decrease stability even when used as an excipient as confirmed in the present invention. In other words, it is difficult to say that the selection of isomalt plays a decisive role in improving the stability of candesartan cilexetil.

Korean Patent Publication No. 10-1460783 claims that the stability of candesartan cilexetil depends on the moisture content inside the formulation, and the loss on drying (LDO) value must be 3.5% or more to significantly reduce the content of related substances, resulting in stability It is disclosed that this is improved. Specifically, the document discloses a method for preparing granules by drying in a fluidized bed dryer with candesartan cilexetil, lactose hydrate, corn starch, carboxymethylcellulose calcium, and colicott ial, followed by sizing; Here is the stability comparison result according to the loss on drying (LDO) value in the drying process. However, if there is a limit on LOD in the production of formulations, the process is not easy, so it is not suitable for production on an industrial scale.

[Candesartan Combination Drug]

It has been reported that in the treatment of hypertension, a combination of drugs with different mechanisms can exert better preventive and therapeutic effects than selecting one drug. Co-administration can reduce the side effects that can occur due to long-term use of drugs by reducing the amount of single drug, and can exert a synergistic effect in blood pressure control as well as cardiovascular protective effects by the complementary action of two or more drugs. .

Commonly known angiotensin II receptor antagonists and calcium channel blockers include amlodipine besylate and atorvastatin calcium, amlodipine besylate and valsartan, amlodipine besylate and benazepril hydrochloride, amlodipine camsylate and simvastatin, amlodipine and telmisartan, and amlodipine. These include camsylate and losartan calcium salt, amlodipine besylate and candesartan cilexetil.

For example, Korean Patent Publication No. 10-1769293 introduces a combination of candesartan cilexetil and amlodipine besylate using liquid triethyl citrate as a stabilizer of candesartan cilexetil.

However, Korean Patent Publication No. 10-1769293 introduces that triethyl citrate and mannitol should be used as a filler, but International Patent Publication No. 2016/122256 has negatively described the use of mannitol as a filler.

Republic of Korea Patent Publication No. 10-1992-0021902 US Patent Publication No. 2008-01188564 Republic of Korea Patent Publication No. 10-2011-0062278 Republic of Korea Patent Publication No. 10-1460783 Republic of Korea Patent Publication No. 10-1769293 International Patent Publication No. 2016/122256

Since candesartan or candesartan cilexetil is a poorly soluble substance, solubilization is basically required when designing a formulation. In addition, since candesartan or candesartan cilexetil is sensitive to stability, stabilization is also required.

In the prior art, for the solubilization and stabilization of candesartan or candesartan cilexetil, an excipient of sugar or sugar alcohol and a solubilizer of colicotta al are mixed, and moisture is reduced so that the loss on drying (LOD) of the granules is 3.5% or more. It is suggested to granulate in the contained state.

However, if the granules contain enough moisture to show a loss on drying of a certain level or more, it is not preferable for tableting during formulation. Specifically, when formulating a single agent of candesartan or candesartan cilexetil, as well as formulating a combination agent with amlodipine, a tableting defect may occur.

Accordingly, the present inventors have completed the present invention capable of achieving satisfactory solubilization and stabilization, unlike the prior art, even if the water content of candesartan or candesartan cilexetil granules is below a certain level in order to improve tabletting properties.

The prescription of candesartan or candesartan cilexetil according to the present invention does not affect the stability of amlodipine when forming a combination drug with amlodipine.

1. A pharmaceutical composition comprising candesartan or candesartan cilexetil, and tocopherol polyethylene glycol succinate (TPGS), wherein the loss on drying for the final composition is less than 6.0% (w/w).

2. The pharmaceutical composition according to 1 above, wherein the content of TPGS is 0.5 to 10% by weight based on the total composition.

3. The pharmaceutical composition according to 1 or 2 above, further comprising starch (eg, starch).

4. The pharmaceutical composition according to any one of 1 to 3, further comprising a cellulose derivative (eg, microcrystalline cellulose, silicified microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and hydroxypropyl cellulose).

5. A composite pharmaceutical composition comprising the pharmaceutical composition according to any one of 1 to 4 and the pharmaceutical composition comprising amlodipine.

One embodiment of the single agent composition of the present invention is excellent in solubilization and stabilization of candesartan or candesartan cilexetil. In particular, since the initial dissolution of candesartan or candesartan cilexetil is excellent, there is an advantage in the expression of efficacy.

One embodiment of the single agent composition of the present invention has excellent tabletting properties. When formulating tablets, a certain level of hardness is achieved, and the defect rate is low.

One embodiment of the composition of the composite agent of the present invention has excellent stability of candesartan or candesartan cilexetil as well as amlodipine.

One embodiment of the composite composition of the present invention has excellent tabletting properties, and layer separation does not occur easily when formulated as a two-layer tablet.

1 is a diagram showing the dissolution rate of candesartan cilexetil.

[Candesartan or candesartan cilexetil single agent]

As used herein, candesartan or candesartan cilexetil includes all preforms or salts thereof. The present invention relates to formulation design and is not suitable only for a specific main ingredient, and can be widely applied to any main ingredient containing candesartan as an active ingredient, so the scope of the main ingredient is not limited below.

As used herein, the loss on drying (LOD) refers to the total amount of free water and other volatile substances in the sample that are lost when dried. For example, the LOD value in the present invention is a value obtained by measuring the weight ratio of reduced free water and other volatile substances when candesartan or candesartan cilexetil formulation is dried at 80° C. for 15 minutes. However, the LOD value is not necessarily measured only under the same conditions as described above, and may be measured under different conditions depending on the physical properties and state of the sample. LOD can be measured using an infrared moisture meter, and can be calculated according to the following equation.

Loss on drying (LOD) (%, w/w) = [(weight before drying - weight after drying) / weight before drying] x 100

The prior art suggested that it is beneficial for stabilization to raise the loss on drying to 3.5% or more. Specifically, it was argued that the content of related substances of candesartan or candesartan cilexetil increased when the drying loss was less than 3.5%. The prescription exemplified in the prior art is as follows.

purpose of mixing ingredient chief ingredient Candesartan cilexetil excipient lactose hydrate excipient corn starch disintegrant Carboxymethylcellulose calcium binder coli coat eye lubricant magnesium stearate coloring agent red iron oxide

However, if the loss on drying is higher than a certain level, the raw tablet having a certain hardness or higher may not be tableted because it contains moisture. That is, a defective rate may occur in tabletting property. From the viewpoint of tabletting properties, it is preferable that the loss on drying is low.

The present inventors surprisingly confirmed that when candesartan or candesartan cilexetil contains TPGS, the stability is excellent even when the loss on drying is less than 6.0%, for example, 3.5% or less.

The present invention is characterized in that the loss on drying of the final mixture is less than 6.0% and at the same time contains TPGS.

TPGS may be blended in 0.5 to 10% by weight based on the total composition in consideration of the tabletting properties of the uncoated tablet, the initial elution of candesartan or candesartan cilexetil, and the stability thereof.

The present invention is preferably characterized in that it further contains starch.

In the prior art, in order to solubilize candesartan or candesartan cilexetil, it has been common to select a sugar or sugar alcohol that is easily soluble in water as an excipient. For example, Korean Patent Publication No. 10-1460783 contains lactose hydrate as a main excipient, and Korean Patent Publication No. 10-2011-0062278 uses isomalt as a main excipient.

However, in the present invention, when the starch was formulated in terms of interaction with TPGS, it was preferable in achieving the objective effect of the present invention. Starch refers, for example, to starch (pregelatinized starch).

Starch may be formulated in an amount of 5 to 15% by weight based on the total composition in consideration of the tabletting properties of the raw tablet, the initial elution of candesartan or candesartan cilexetil, and the stability thereof.

In addition, the present invention may further include additional excipients, binders, disintegrants, lubricants, and the like.

The additional excipient may be selected from sugars, lactoses, celluloses, starches, and the like, and more preferably, cellulose derivatives from celluloses. Examples of the cellulose derivative include microcrystalline cellulose, silicified microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and hydroxypropyl cellulose.

Additional excipients may be formulated in an appropriate amount so that the size of the final uncoated tablet does not become too large.

In one embodiment of the present invention, the excipient may be blended when forming granules of candesartan or candesartan cilexetil, and may be blended after mixing with the lubricant.

The binder is polyvinylpyrrolidone vinyl acetate, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylic acid, gelatin, propylene glycol, alginic acid. Any known component such as sodium can be selected.

The binder may be formulated in an amount generally selected by a person skilled in the art in consideration of the characteristics of each component in forming granules.

The disintegrant may be selected from any known component such as croscarmellose sodium, crospovidone, carboxymethylcellulose salt (eg, carboxycellulose calcium, sodium carboxycellulose), hydroxypropyl cellulose, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, etc. have.

The disintegrant promotes disintegration and may be formulated in an amount generally selected by a person skilled in the art in consideration of the characteristics of each component in a range that does not affect the stability of the main component.

As the lubricant, any known component such as magnesium stearate, sodium stearyl fumarate, and glyceryl behenate may be selected.

The lubricant may be formulated in an amount generally selected by a person skilled in the art in consideration of flowability.

The present invention is characterized by wet granulation of candesartan or candesartan cilexetil. A well-known manufacturing method can be used for the granulation method.

combining, for example, candesartan or candesartan cilexetil, TPGS, starch, additional excipients, disintegrants into a binding solution comprising a binding agent; drying the association product; establishing a dry matter; post-mixing a lubricant and an additional excipient to the sized product; and tableting the mixture. In the present invention, the stability of candesartan or candesartan cilexetil is sufficiently guaranteed even if the loss on drying is less than 6.0%, for example, 3.5% or less.

Drying conditions, particle size at the time of sizing, tableting conditions, etc. can be carried out by a known method.

[Candesartan or candesartan cilexetil and amlodipine combination]

The composition and manufacturing method for candesartan or candesartan cilexetil single agent described above can be applied to the design of a combination drug with amlodipine as it is.

As used herein, amlodipine includes all of its optical isomers, preforms or salts thereof. The present invention relates to formulation design and is not suitable only for a specific main ingredient, and can be widely applied to any main ingredient containing amlodipine as an active ingredient, so the scope of the main ingredient is not limited below.

The most important thing when forming a combination drug is that a matrix formulation suitable for a specific active ingredient should not adversely affect other active ingredients. However, it is known that some of the additives used in candesartan or candesartan cilexetil may react with amlodipine to produce amlodipine degradation products. In consideration of this, Republic of Korea Patent Publication No. 10-1769293 introduces a combination of candesartan or candesartan cilexetil stabilizer of triethyl citrate and mannitol excipient.

However, the present inventors confirmed that, in the case of candesartan or candesartan cilexetil, the prescription according to the present invention described above is the most preferable in tabletting performance, initial dissolution and stability, and furthermore, the prescription does not negatively affect the stability of amlodipine. said

The present invention is characterized in that it is a combination composition comprising the aforementioned candesartan or candesartan cilexetil composition and an amlodipine composition.

The composite agent may be prepared as a single-layer tablet or a double-layer tablet, and a known method may be applied for each preparation method.

The present invention will be described in more detail with reference to the following examples. However, the examples are only some implementations of the present invention, and the present invention is not limited thereto.

[Example]

Stability test of candesartan cilexetil according to additives

A kneading solution was prepared according to Example 1 and Comparative Examples 1-4, and after mixing candesartan cilexetil, microcrystalline cellulose, pregelatinized starch, and croscarmellose sodium, the kneading solution was added and kneaded. After drying, silicified microcrystalline cellulose and magnesium stearate were mixed and tableted to prepare tablets.

Example 1

Hydroxypropyl cellulose and tocopherol polyethylene glycol succinate were dissolved in a solvent to prepare a combined solution.

Comparative Example 1

Hydroxypropyl cellulose and butylhydroxytoluene were dissolved in a solvent to prepare a kneaded solution.

Comparative Example 2

Hydroxypropyl cellulose and butylhydroxyanisole were dissolved in a solvent to prepare a kneaded solution.

Comparative Example 3

Hydroxypropyl cellulose and citric acid hydrate were dissolved in a solvent to prepare a kneaded solution.

Comparative Example 4

Hydroxypropyl cellulose and polyethylene glycol 6000 were dissolved in a solvent to prepare a kneaded solution.

Butylhydroxytoluene, butylcydoxyanisole, citric acid hydrate, and polyethylene glycol 6000 of Comparative Examples 1 to 4 are commonly used known stabilizers.

Raw material name Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 ratio(%) ratio(%) ratio(%) ratio(%) ratio(%) Candesartan cilexetil 10.0 10.0 10.0 10.0 10.0 Microcrystalline Cellulose 49.3 49.3 49.3 49.3 49.3 pregelatinized starch 9.4 9.4 9.4 9.4 9.4 Hydroxypropyl Cellulose 4.4 4.4 4.4 4.4 4.4 Croscarmellose Sodium 3.8 3.8 3.8 3.8 3.8 Tocopherol polyethylene glycol succinate 5 Butylhydroxytoluene 5 Butylhydroxyanisole 5 citric acid hydrate 5 Polyethylene glycol 6000 5 Silica Microcrystalline Cellulose 17.5 17.5 17.5 17.5 17.5 magnesium stearate 0.6 0.6 0.6 0.6 0.6 Sum 100.0 100.0 100.0 100.0 100.0

Stability test

Storage conditions: 60℃, RH80%, storage for 2 weeks

operating conditions

- Detector: Ultraviolet absorbance spectrometer (measurement wavelength: 253 nm)

- Column: A column filled with 5 μm octadecylsilyl silica gel for liquid chromatography in a stainless steel tube with an inner diameter of about 4.6 mm and a length of about 15 cm, and an equivalent column

- mobile phase

Mobile phase A) Water, acetonitrile, trifluoroacetic acid = 800 : 200 : 0.2

Mobile phase B) Acetonitrile Water Trifluoroacetic acid = 800 : 200 : 0.2

hours (minutes) Mobile phase A (%) Mobile phase B (%) 0 100 0 25 50 50 60 10 90 65 10 90 66 100 0 72 100 0

The related substances produced by decomposition from candesartan are total related substances a, b, c, d, e, and f, and representative related substances are b and f.

Related substances b

O-Desethyl Candesartan Cilexetil
(CAS no. 869631-11-8) related substances f

2-Ethyl Candesartan Cilexetil
(CAS no. 914613-36-8)

Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Related substance b increase (%) 0.16 0.22 9.23 0.23 3.18 Related substances f increase (%) 0.11 0.18 6.77 0.35 2.99 Total flexible material increase (%) 0.29 0.43 30.05 0.65 10.97

TPGS is a component known as a solubilizer rather than a stabilizer, and in the present invention, it showed an unexpected effect of inhibiting the generation of related substances of candesartan rather than a known antioxidant or stabilizer.

Stability test of candesartan cilexetil according to tocopherol polyethylene glycol succinate content

contrast example

A commercial product containing candesartan was used as a control.

Comparative Example 5

Hydroxypropyl cellulose was dissolved in a solvent to prepare a kneaded solution. After mixing candesartan cilexetil, microcrystalline cellulose, and croscarmellose sodium, kneading solution was added to knead the mixture, and after drying, silicified microcrystalline cellulose and magnesium stearate were mixed and tableted to prepare tablets.

Comparative Example 6

Hydroxypropyl cellulose was dissolved in a solvent to prepare a kneaded solution. After mixing candesartan cilexetil, microcrystalline cellulose, pregelatinized starch, and croscarmellose sodium, kneading solution was added to knead the mixture, and after drying, silicified microcrystalline cellulose and magnesium stearate were mixed and tableted to prepare tablets.

Example 2

Hydroxypropyl cellulose and tocopherol polyethylene glycol succinate were dissolved in a solvent to prepare a combined solution. After mixing candesartan cilexetil, microcrystalline cellulose, and croscarmellose sodium, kneading solution was added to knead the mixture, and after drying, silicified microcrystalline cellulose and magnesium stearate were mixed and tableted to prepare tablets.

Example 3-5

Hydroxypropyl cellulose and tocopherol polyethylene glycol succinate were dissolved in a solvent to prepare a combined solution. After mixing candesartan cilexetil, microcrystalline cellulose, pregelatinized starch, and croscarmellose sodium, kneading solution was added to knead the mixture, and after drying, silicified microcrystalline cellulose and magnesium stearate were mixed and tableted to prepare tablets.

Example 6

Hydroxypropyl cellulose and tocopherol polyethylene glycol succinate were dissolved in a solvent to prepare a kneading solution. When the concentration of tocopherol polyethylene glycol succinate was high, 15 wt %, a binding solution could not be prepared.

Raw material name Comparative Example 5 Comparative Example 6 Example 2 Example 3 Example 4 Example 5 Example 6 ratio(%) ratio(%) ratio(%) ratio(%) ratio(%) ratio(%) ratio(%) Candesartan cilexetil 10.0 10.0 10.0 10.0 10.0 10.0 10.0 Microcrystalline Cellulose 54.4 53.9 54.4 49.4 54.4 44.4 39.5 pregelatinized starch - 9.4 - 9.4 9.4 9.4 9.4 Hydroxypropyl Cellulose 4.4 4.4 4.4 4.4 4.4 4.4 4.4 Croscarmellose Sodium 3.8 3.8 3.8 3.8 3.8 3.8 3.8 Tocopherol polyethylene glycol succinate - - 10.0 0.5 5.0 10.0 15.0 Silica Microcrystalline Cellulose 17.5 17.5 17.5 17.5 17.5 17.5 17.5 magnesium stearate 0.6 0.6 0.6 0.6 0.6 0.6 0.6 Sum 100.0 100.0 100.0 100.0 100.0 100.0 100.0

contrast example Comparative Example 5 Comparative Example 6 Example 2 Example 3 Example 4 Example 5 Related substance b increase (%) 0.21 1.21 1.10 0.15 0.47 0.16 0.15 Related substances f increase (%) 0.19 0.82 0.79 0.12 0.33 0.11 0.10 Total flexible material increase (%) 2.85 3.21 3.02 0.30 1.08 0.29 0.27

The stability effect of Example 2 containing TPGS was superior to those of Comparative Examples 5 and 6 containing no TPGS, and the stability data of Example 5 in which TPGS and starch (pregelatinized starch) were combined was the best. Although the exact reason for the results of Example 5 is unknown, it is assumed that TPGS exhibits an unknown synergistic effect with starch (pregelatinized starch) and the like.

Stability and tabletting test of candesartan cilexetil according to loss on drying

Examples 7-11

Based on the composition of Example 4, by varying the drying time of the kneaded product dried at 60° C., tablets were prepared so that the loss on drying of the final mixture was about 1 to 7%.

Comparative Examples 7 - 8

Tablets were prepared so that the drying time of the mixture dried at 60° C. was changed so that the loss on drying of the final mixture was about 1 to 7%.

Loss on drying was measured at 80 °C for 15 minutes.

Example 7 Example 8 Example 9 Example 10 Example 11 Comparative Example 7 Comparative Example 8 Loss on drying (%) 1.4 2.2 3.1 4.0 5.3 6.0 7.2 Related substance b increase (%) 0.14 0.16 0.15 0.15 0.17 0.14 0.16 related substances f
Increase (%) 0.15 0.11 0.14 0.16 0.17 0.17 0.20 Total flexible material increase (%) 0.32 0.30 0.29 0.33 0.35 0.33 0.31

It was confirmed that the amount of increase in total flexible substances was insignificant in Examples 7-11 and Comparative Examples 7-8 containing tocopherol polyethylene glycol succinate regardless of the loss on drying of the final mixture.

Tablets were manufactured by applying the same compression pressure to the mixtures of each Example prepared for each weight loss on drying, and then tabletting properties were evaluated by measuring hardness. If the hardness of the tablet is weak, there is a risk of destruction during coating or storage and transportation, so the tabletting property was evaluated based on 5 kP. When the loss on drying was about 6%, the hardness was 5 kP or less, and it was confirmed that the preferred range of the loss on drying was less than 6%.

Example 7 Example 8 Example 9 Example 10 Example 11 Comparative Example 7 Comparative Example 8 Hardness (kP) 9.5 9.8 9.3 9.0 7.2 4.5 3.6

Increase in dissolution rate of candesartan cilexetil with tocopherol polyethylene glycol succinate

The dissolution rate of candesartan cilexetil was increased in Example 5 in which tocopherol polyethylene glycol succinate was not added compared to Comparative Example 6 in which tocopherol polyethylene glycol succinate was not added, and the initial dissolution rate of candesartan cilexetil in Example 5 was higher than in Example 2 by the inclusion of pregelatinized starch. It was confirmed that there was an increase (FIG. 1).

Tocopherol polyethylene glycol succinate without affecting amlodipine stability

A kneading solution was prepared according to Example 12 and Comparative Examples 9-10, and after mixing candesartan cilexetil, microcrystalline cellulose, pregelatinized starch, and croscarmellose sodium, the kneading solution was added and kneaded. After drying, silicified microcrystalline cellulose and magnesium stearate were mixed and tableted to prepare tablets.

Example 12

Hydroxypropyl cellulose and tocopherol polyethylene glycol succinate were dissolved in a solvent to prepare a combined solution.

Comparative Example 9

Hydroxypropyl cellulose and butylhydroxytoluene were dissolved in a solvent to prepare a kneaded solution.

Comparative Example 10

Hydroxypropyl cellulose was dissolved in a solvent to prepare a kneaded solution.

Raw material name Example 12 Comparative Example 9 Comparative Example 10 ratio(%) ratio(%) ratio(%) Candesartan cilexetil 5.0 5.0 5.0 amlodipine 4.3 4.3 4.3 Microcrystalline Cellulose 58.8 58.8 58.8 pregelatinized starch 4.7 4.7 4.7 Hydroxypropyl Cellulose 2.2 2.2 2.2 Croscarmellose Sodium 1.9 1.9 1.9 Tocopherol polyethylene glycol succinate 2.5 - - Butylhydroxytoluene - 2.5 - Silica Microcrystalline Cellulose 8.8 8.8 8.8 copovidone 3.4 3.4 3.4 star cap 7.8 7.8 7.8 magnesium stearate 0.6 0.6 0.6 Sum 100.0 100.0 100.0

In Comparative Example 9 in which butylhydroxytoluene was added, it was confirmed that the increase in the total amount of amlodipine related substances was 1.45%, which was higher than in Example 12.

Example 12 Comparative Example 9 Comparative Example 10 Candesartan Related substance b increase (%) 0.19 0.25 1.08 Related substances f increase (%) 0.15 0.22 0.88 Total flexible material increase (%) 0.38 0.51 3.5 amlodipine Related substances A increase (%) 0.03 0.61 0.2 Total flexible material increase (%) 0.13 1.45 0.74

Claims (4)

It contains candesartan or candesartan cilexetil, and tocopherol polyethylene glycol succinate (TPGS), and the content of TPGS is 0.5 to 10% by weight based on the total composition, and the loss on drying for the final composition is less than 6.0% (w/w) pharmaceutical composition. delete The pharmaceutical composition according to claim 1, further comprising pregelatinized starch. A composite pharmaceutical composition comprising the pharmaceutical composition according to claim 1 and the pharmaceutical composition comprising amlodipine.

Images